Development of the Cardiovascular System

DevelopmentoftheCardiovascularSystem—Introduction

The development of the cardiovascular systemisan early embryological event. It begins during the third week of gestation or the fifth week LMP.

Fromfertilization, it takes five weeks for thehuman heart to develop into its definitive fetal structure. During this period, the systemdevelops so it can:

-Supply nutrients and oxygen to the fetus

-Immediately function after birth

The heart first begins as a horseshoe shaped pericardial cavitywith an inner endocardial

tube. This endocardial heart tube isthensurrounded by visceral mesodermwhich will become the myocardial mantle. The two endocardial heart tubes fuse and the fused single heart tube begins to beat at approximately 21 days of gestation.

Then the heart tube convolutes and a primitive heart is established the end ofthe first month of gestation or 6 weeks LMP. This heart can be described ashaving three regions: an inflow tract, the cardiac chambers, and an outflow tract.

Finally,theheartundergoes septation and the four chambers ofthe heart are established by 37 days after gestation or 7 weeks LMP.

EarlyDevelopmentoftheCirculatorySystem

CardiacMuscle Cells

During gastrulation, the cells that will give rise to the heart move to an anterior and lateral position of the mesoderm.

It appears that signals fromthe endoderm may cause the expression of cardiac specific genes that allow for the differentiation of mesodermal cells into cardiac muscle cells. BMP2,4 in the endoderm and crescent, a WNT inhibitor, are co-expressed and where they overlap induce NKX2.5 in the mesodermwhich is necessary for heart induction.

Very early in development the cardiac musclecells are organized in a cephalo-caudal direction.

The more cephalic cells will become the outflow tract ofthe heart and the more caudal cells will be located at the inflow region.

HeartTube

In the embryo, a horseshoe-shaped prospective pericardial cavityis located in a precephalic position, rostral to the oral and neural plate.

By the middle ofthe third week ofgestation cardiac muscle cells in the visceral

(splanchnic)mesodermforma plexus of vessels which develop into a horseshoe-shapedendocardial heart tube. These vessels lie deep to the pericardial cavity.

The lateral plate visceral mesodermproliferates, surrounds the endocardial heart tubes, and develops into the myocardium.

The epicardium develops fromcells that migrate over the myocardial mantle fromareas adjacent to the developing heart.

The heart tube consists ofanendocardiallayersurrounded by the myocardiumwith an intervening layer ofextracellular matrix, sometimes called the cardiac jelly.

The cephalic ends of the endocardial heart tubes connect in the midline and also connect via aortic arches, with a pairof newly forming vessels, the dorsal aortae, located on either side ofthe midline.

The caudal ends of these endocardial heart tubes continue to develop and soon connect to the umbilical veins developing in the yolk stalk.

As the embryo undergoes lateral body folding,head and tail folding, and cephalic growth of the brain, there is a shift of the endocardial heart tubes medially, ventrally and caudally. They fuse in the midline as a singleendocardial heart tube. The resulting heart tube is suspended in the pericardial cavity by the dorsal mesocardium.

When the single heart tube is formed, the embryo is at the beginning of the fourth week

ofgestation, is about 3 mm in length, has 4 - 12somites, and the neural tube is beginning to form. The heart now begins to beat.

VascularCircuits

Asthe heart begins to beat, blood islands coalesce to formthree vascular circuits.

Within the embryo an embryonic circuit forms.It consists of paired dorsal aortae that arise fromthe endocardial heart tube and breakup into capillary networks that supply blood to the developing embryonic tissues.Blood is drained fromthese tissues by anterior and posterior cardinal veinsthat draininto common cardinal veins, which in turn drain into the endocardial heart tube.

Two extraembryonic circuits also form.

1. The first is thevitellinecircuit. In this circuit,blood fromthe dorsal aortae flows into vitelline arteries that supply the yolk sac. The blood drains back to the heart tube via paired vitelline veins.

2. The second extraembryonic circuit is theumbilical circuit. Here the dorsal aortae supply blood to umbilical arteries thatin turn bring this now deoxygenated blood back to the placenta. Blood fromthe placenta is carried to the heart tube via umbilical veins.

FormationofthePrimitive FourChamberedHeart

HeartTube Dilation

As the endocardial heart tube fuses, several bulges and sulci appear. From the caudal to the cephalic end, the bulges are:

-Sinus venosus. This is the inflow tract ofthe heart tube. Blood flows into the sinus venosus via the veins.

-Primitive atrium

-Primitive ventricle

-Bulbus cordis, which consists of the aortic sac,the

truncusarteriosus and the conus arteriosus. This is

theoutflow tract of the heart tube. Paired dorsal aortae arise fromaortic archesthat in turn arise fromthe aortic sac. The aortic sac is at the most cephalic end of the bulbus cordis.

The sulci present are the bulboventricular sulcus, between the bulbus cordis and the ventricle, and theatrioventricular sulcus, between the atrium and the ventricle.

Looping

Therenow occurs a rapid growth of the heart tube and the heart begins to loop anteriorly and to the right. This is important for the proper alignment of the inflow and outflow tracts with the cardiac chambers.

During the process of convolution, the first flexure seen is between the bulbus cordis and the ventricle. Thebulboventricularloopshifts this region of the heart to the right and ventrally.

The second flexure, atrioventricular loop, is between the atriumand the ventricle and this region ofthe heart isshifted to the left and dorsally.

As growth continues, the atria shift cephalically and begin to bulgeforward on either side of the bulbus cordis, shifting the bulbus medially. The sinus venosus shifts to the right to empty into the right atrium.

During convolution, thedorsal mesocardium begins to degenerate, leaving a space that becomes the transversesinus.

The atrioventricular canalis the opening that remains after convolution of the heart tube, which connects theprimitive atriumto the primitive ventricle. The canal shifts to the right during the stages after convolution.Initially, the common atria are located over the primitive ventricle. However, there isa shifting ofthe AV canal to the right that subsequently aligns the atria over the bulbus cordis and primitive ventricle. The AV canal is thenseparated into a right and left side.

The bulboventricular sulcus is represented inside the heart as thebulboventricular flange. The bulboventricular flange and the muscular interventricular septumseparate the primitive ventricle (which will become theleft ventricle) fromthe conus arteriosus (which will become the definitive right ventricle). The bulboventricular flange later regresses leaving a cephalicallylocated hole in the IV septum, called the IV foramen.

HeartTube Dilatation / AdultStructure
Truncusarteriosus / Aortaand Pulmonary Artery
ConusArteriosus / RightVentricle
Primitive Ventricle / Left Ventricle
Primitive Atrium / Trabeculated Portion ofLeftand Right Atrium
SinusVenosus / Smooth Portion of Right Atrium, Coronary
Sinus,Oblique Vein of Marshall
Pulmonary Vein / Smooth portion of Left Atrium

Mechanismsof Looping

The mechanismfor this convolution processis not well understood. However it is clear there is an asymmetric expression ofdifferent cell-cell signaling molecules. For example, Nodal is expressed onthe left side with Snr1 expressed on the right. How this relates to looping is unknown. Looping is one of the firstexamples of asymmetry within the embryo.

It does appear that the cytoskeleton is important in the looping process.Recent evidence suggests that early in development, cells in the cardiac region with defective cilia will not convolute properly. Thus early on cilia help establish a gradient within the extracellular matrix that guides the convolution process.

SeptationoftheHeart

Duringthe second month, the heart begins toundergo septation into two atria, two ventricles, theascending aorta and the pulmonary trunk.

AtrialSeptation

Formationof the Atrioventricular Septum

Endocardial cushions develop in the dorsal (inferior) and ventral (superior) walls ofthe cardiac atrioventricular canal.

Specific cells fromthe endocardiumare inducedby the myocardial cells and migrate into the extracellular matrix tissue in between the endocardiumand myocardium. These cells will be found not only inthe region ofthe AV canal but also a similar population ofcells is found in the outflow tract region. These mesenchymal cells will beginto differentiate along different lines according to the structure that they will develop into.

In the region of the AV canal, one group of the mesenchymal cell population grows and populates the two cushions which then grow toward each other.

These cushions fuse and divide the common AV canal intothe leftand right AV canals.

VentralAV Cushion

DorsalAV Cushion

Formationof the Atrial Septum

As the endocardial cushions develop, there is a developingseptumfromthe dorsocranial atrial wall that grows towardthe cushions. This is theseptum primum, and the intervening space is called theforamen primum.

As the septumreaches the endocardial cushions closing foramen primum, a second opening, foramen secundumappears in septumprimum. This is necessary to permit flow of blood fromthe developing right atriumto the developing left side of the heart. As foramen secundumenlarges, via apoptosis or programmed cell death, a second septum, septum secundumforms to the right of septumprimum.

Septumsecundumforms an incomplete partition (lying to the right of foramen

secundum) that leaves an opening, theforamen ovale. The remaining portions of septum primumbecome the valve of foramen ovale.

RightAtrium

Concurrently, the sinus venosus has shifted to the right. The right sinus venosus becomes incorporatedinto the right atriumformingthe smooth portion of the right atrium.

The primitive right atriumis seen in the adult as the rough portion (auricle) of the right atrium.

The remainder of the left sinus venosus is thecoronary sinus and the oblique vein (of

Marshall)in the adult heart.

LeftAtrium

On the left side, the primitive atriumis enlarged by the incorporation oftissue fromthe original, single pulmonary veinand its proximal branches.The vein develops in the mediastinum fromblood islands that coalesce. These newly formed vessels branch as they develop in the developing lung tissue.

In the region of the left atrium, these vessels become reabsorbed into the left atriumand the tissue is incorporatedand becomes the adult smooth left atrial wall. The vessels

become reabsorbed up to the second branch point, which then leaves four pulmonary veins emptying independently into the left atrial chamber.

The trabeculated left atrial appendage is a remnant ofthe primitive left atrium.

VentricularSeptation

Theendocardial cushions eventually lie opposite the developing interventricular septum. The septumis the inward manifestation of the bulboventricular sulcus.

The muscular interventricular (I.V.) septumgrows as a ridge of tissue fromthe caudal heart wall toward the fused endocardial cushions.

The interventricular foramenis the opening remainingbetween the muscular IV

septumand the fused endocardial cushions.

This foramen is closed by the membranous part of the interventricular septum,which is formed by the fusion of tissue from three sources:

-Conal ridges,

-An outgrowth of the inferior endocardial cushion - the right tubercle

-Connective tissue fromthe muscular interventricular septum

Septationof the Bulbus Cordis

Truncal and conal septa fuse to forman 180o spiraland together definitively formthe aorta and the pulmonary artery.

-Truncal swellings (ridges) appear first as bulges inthe truncus on the right superior andthe left inferior walls. They enlarge and fuse inthe midline to form the truncal(aorticopulmonary)septum.This septumseparates the distal pulmonary artery fromthe aorta.

-At the same time right dorsal and left ventral conal ridges form and fuse in the midline. The conal septum helps divide the proximal aorta fromthe pulmonary artery and contributes to the membranous IV septum.

Cells that contribute to the conal andthe truncal septa are inpartderivedfromneural crestcells that migrate into these regions.

Atthis point in development (day 35 of gestation or 7 weeks LMP), the right atriumis in communication with the conus arteriosus, which is now the right ventricle. The left atriumis in communication with the primitive ventricle, which isnow the left ventricle.The right and left atria remain in communication via the foramen ovale and ostiumsecundum. Thus, the primitive four-chambered heart is formed and blood flows from the veins to sinus venosus, to atria, to ventricles, to truncus, toaortic sac, and then to dorsal aorta.

CardiacValve Formation

Semilunarvalves develop in the aorta and pulmonaryartery as localized swellings of endocardial tissue.

The atrioventricular valves develop as subendocardial and endocardial tissues and project into the AV canal.

These bulges are excavated fromthe ventricular side and invaded by muscle. Eventually, the valve will be constituted fromboth connective tissue and myocardial tissue. In addition, muscle cells will make up a large part of thepapillary muscle which attaches to the valve leaflets.

The remodeling of the AV canal cushion tissue results in three cusps oftheright AV (tricuspid)valve, and two cusps of theleft AV (mitral) valve.

The atrial myocardiumis separated fromthe ventricular myocardiumby connective tissue except in the region of the AV node and bundle.

There are growth factorsthat are associatedwith the development of the endocardial cushions. Growth factors such as members of the Fibroblast Growth Factor and Insulin- like growth factor families as well asother factors such as BMP-2, Smad6, NF-Atc, and Sox4 may play important roles in the development of the valves and the connective tissue that separates ventricular and atrial tissue.

The separation of these tissues is important, as extra connections betweenthe atrial and ventricular chambers can lead to the generation of cardiac arrhythmias.

DevelopmentoftheCardiacConductionSystem

Theconduction systemregulates the electrical activity of the heart. It consists of the sinoatrial node, the atrioventricular node, theatrioventricular bundle (of His),the left and right bundle branches, and the Purkinje fibers.

The sinoatrial nodeand the atrioventricular nodedevelop from regions of the heart tube that have slow conducting properties. This explains why the AV node is a region where conduction velocities slow beforearriving at the AV bundle.

The AV bundle and the Purkinje fibers arise from fast conducting working myocardium.

Thesecells are found near the developing coronary vessels and perhaps under the influence of the growth factor endothelin-1(ET-1), they differentiate into the bundle branches and the Purkinje fibersthatconnecttheAVbundleto the working myocardium. However the exact influences that regulatethe development of conduction systemare not known.

The six pairs ofaortic arches, develop in a cephalo-caudaldirection and interconnect the

ventralaortic rootsandthedorsal aorta.

They are never all present in the developinghuman heart. Of the six pairs of aortic

arches,most of the first, second and fifth arches disappear. The fate of the arches, ventral roots and the dorsal aorta are listed below.

STRUCTURERIGHTLEFT

1stAorticArch / Mostdisappear (some forms maxillary art.) / Mostdisappear (some forms maxillary art.)
2ndAorticArch / Mostdisappears / Mostdisappears
3rdAorticArch / Proximal internal carotid artery / Proximal internal carotid artery
CranialDorsal Aorta / Distalinternalcarotidartery / Distalinternalcarotidartery
VentralAorta between 3rd and 4th Arch / Commoncarotid artery / Commoncarotid artery
VentralAortic Root to 4th
Arch / Brachiocephalicartery / Ascendingaorta
DorsalAorta between 3rd and 4th Arch / Disappears / Disappears
4thAortic Arch / Proximal right subclavian artery / Archof aorta
DorsalAorta between 4th arch and 7thintersegmental artery / Middleof the subclavian artery / Distalarch ofthe aorta
7thintersegmental artery / Distalsubclavian artery / Subclavianartery
5thAortic Arch / Neverdeveloped / Neverdeveloped
Proximal 6th Aortic Arch / Proximal right pulmonary artery / Proximal left pulmonary artery
Distal6th Aortic Arch / Disappears / Ductusarteriosus
DorsalAorta below 7th Intersegmental artery to the Junction of the Dorsal Aorta / Disappears / Descendingaorta

The veins develop in a much more variable waythan the arteries. An initial anterior and posterior cardinal systemof veins provides venous drainage for the fetus. New subcardinal veins and supracardinal veins develop as a consequence of the changes found in the abdomen of the developing embryo.

The formation of the liver and the mesonephric kidney has profound affects in redirecting blood flow. The enlarging liver encroaches upon the developingvitellineandumbilical veins and gradually all the blood will drain to the proximal right vitelline vein. The distal vitelline veins will give rise to theportal system. The left umbilical vein remains and drainsintotheductus venosus, a shunt that allows bloodto bypass the developing liver and which empties into the proximal right vitelline vein.

Superiorand Inferior Vena Cava

STRUTURERIGHTLEFT